Affinage

TSHR

Thyrotropin receptor · UniProt P16473

Length
764 aa
Mass
86.8 kDa
Annotated
2026-04-28
100 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TSHR is a G protein-coupled receptor that transduces TSH signaling through multiple heterotrimeric G proteins—primarily Gαs/cAMP/PKA/CREB, but also Gαq and Gα12/13—to control thyroid hormone biosynthesis, iodide transport, and follicular cell proliferation, with the transcription factor GLIS3 acting as a critical downstream mediator linking TSH/TSHR to mTORC1 activation and thyroid-specific gene expression (PMID:29083325, PMID:21677043, PMID:34650915). The extracellular leucine-rich repeat domain binds TSH through contacts on its concave surface and hinge region, and stimulating versus blocking autoantibodies engage this surface in nearly opposite orientations, as resolved by crystal structures with M22 and K1-70 (PMID:21247981, PMID:21628383). Beyond the thyroid, tissue-specific knockouts demonstrate direct roles for TSHR in adipocyte lipolysis and differentiation, hepatic lipid metabolism, and—in the tumor microenvironment—promotion of CD8+ T cell exhaustion via PKA/CREB-dependent upregulation of PD-1 and TIM3 (PMID:20152797, PMID:29421660, PMID:39285586). Germline gain-of-function mutations cause hereditary non-autoimmune hyperthyroidism, while loss-of-function mutations cause congenital hypothyroidism, and TSHR intron-1 variants that reduce thymic expression predispose to Graves' disease through impaired central tolerance (PMID:11201847, PMID:18727713, PMID:21642385).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 Medium

    Defining the autoantibody epitope on the TSHR ectodomain established that residues 90–165 of the N-terminal extracellular region are both necessary and sufficient for induction and recognition of Graves' disease TSH receptor autoantibodies, framing the structural basis of autoimmunity.

    Evidence TSHR/LH-CGR chimeric receptor immunization in mice with functional TBII and TBAb assays

    PMID:9528975

    Open questions at the time
    • epitope mapping used chimeric receptors rather than atomic-resolution structures
    • did not resolve stimulating vs blocking antibody binding modes
  2. 2000 Medium

    Identification of a germline constitutively activating mutation (Met463Val) demonstrated that single residue changes in the transmembrane domain can lock TSHR in an active conformation, establishing the molecular basis of hereditary non-autoimmune hyperthyroidism.

    Evidence Sanger sequencing of patient DNA with functional cAMP assay in transfected cells

    PMID:11201847

    Open questions at the time
    • structural mechanism of constitutive activation not resolved
    • limited to one mutation; spectrum of activating mutations not fully mapped at that time
  3. 2008 High

    Systematic functional characterization of six novel TSHR mutations in congenital hypothyroidism patients established genotype-function relationships, showing that mutations at different positions (extracellular vs transmembrane) differentially impair TSH binding and cAMP signaling.

    Evidence Site-directed mutagenesis with 125I-TSH binding, cAMP assay, and surface expression in COS cells

    PMID:18727713

    Open questions at the time
    • Gq pathway not assessed for these mutations
    • no structural models to explain differential effects
  4. 2010 High

    Two key advances resolved TSHR regulation and extrathyroidal function: adipocyte-specific TSHR knockout proved a direct, non-thyroid role in lipolysis, while discovery that cleaved β-subunits dimerize with full-length TSHR and dampen TSH-induced cAMP revealed a novel negative-feedback mechanism at the receptor level.

    Evidence Cre-loxP adipocyte-specific KO with lipolysis assays; co-IP, FRET, and cAMP assays in HEK293 cells

    PMID:20152797 PMID:20719860

    Open questions at the time
    • in vivo relevance of β-subunit dimerization not demonstrated
    • adipocyte KO did not distinguish downstream Gs vs Gq contributions
  5. 2011 High

    A convergence of structural, mutagenesis, and genetic studies resolved how TSH and autoantibodies engage the ectodomain: the K1-70 crystal structure showed blocking antibodies bind ~155° rotated relative to stimulating antibody M22, hinge-region mutagenesis identified F381–D386 as a TSH contact domain, differential Gs/Gq coupling of inactivating mutations explained paradoxical clinical phenotypes, and reduced thymic TSHR expression from a risk allele linked impaired central tolerance to Graves' disease.

    Evidence X-ray crystallography at 1.9 Å; systematic mutagenesis of 41 hinge residues; dual Gs/Gq functional assays; allele-specific transcript quantification in human thymus

    PMID:21247981 PMID:21628383 PMID:21642385 PMID:21677043

    Open questions at the time
    • full-length TSHR structure including transmembrane domain not resolved
    • mechanism by which antibody orientation determines stimulating vs blocking activity not fully explained
  6. 2012 Medium

    Functional studies in extrathyroidal cells established TSHR as a required driver of adipocyte differentiation and as the exclusive mediator of cAMP-dependent inflammatory cytokine production in Graves' orbital fibroblasts, broadening TSHR's disease-relevant roles beyond thyroid hormone synthesis.

    Evidence siRNA knockdown in 3T3-L1 with adipogenesis markers; TSHR antagonist Org-274179-0 dose-response in primary orbital fibroblasts; PDGF-induced TSHR upregulation with blocking antibody controls

    PMID:22289392 PMID:22419705 PMID:22438231

    Open questions at the time
    • downstream signaling branch (Gs vs Gq vs β-arrestin) mediating adipogenesis not resolved
    • orbital fibroblast studies did not address IGF-1R cross-talk in detail
  7. 2015 Medium

    TSH/TSHR signaling was shown to regulate adipocyte lipid metabolism (suppressing FASN via PKA/CREB and ERK) and orbital fibroblast proliferation (via PI3K/Akt and miR-146a/miR-155), demonstrating pathway-specific downstream effects in different extrathyroidal cell types.

    Evidence Pharmacological inhibitors with Western blot and qPCR in adipocytes; siRNA, BrdU assay, and PI3K inhibitor in orbital fibroblasts

    PMID:25655684 PMID:31622470

    Open questions at the time
    • miR-146a/155 regulation not shown to be direct
    • adipocyte FASN regulation studied in vitro only
  8. 2017 High

    Identification of GLIS3 as a required downstream effector of TSH/TSHR that activates mTORC1 and directly regulates iodide transporter genes (NIS, PDS) provided a transcriptional framework linking receptor activation to thyroid-specific gene expression and proliferation.

    Evidence ChIP-Seq, promoter analysis, and conditional knockout mouse model

    PMID:29083325

    Open questions at the time
    • how GLIS3 integrates with cAMP/PKA vs Gq branches not fully delineated
    • relevance to human thyroid disease beyond mouse model not confirmed
  9. 2018 High

    Liver-specific TSHR knockout reduced hepatic triglyceride and cholesterol content without affecting systemic energy metabolism, establishing a direct hepatocyte-autonomous role for TSHR in lipid homeostasis distinct from thyroid hormone effects.

    Evidence Cre-loxP liver-specific knockout with lipid measurements and metabolic chamber analysis

    PMID:29421660

    Open questions at the time
    • downstream signaling pathway in hepatocytes not dissected
    • human relevance of hepatic TSHR signaling not established
  10. 2021 Medium

    Two studies expanded non-canonical TSHR coupling: in dedifferentiating thyroid cancer, TSH/TSHR shifts from Gαs to Gα12/13-RhoA via LARG to promote migration, while in Schwann cells, palmitoylation of TSHR was identified as a post-translational modification required for TSH-induced oxidative stress and apoptosis.

    Evidence Signaling pathway analysis and LARG expression in thyroid cancer cell lines; TSHR KO and palmitoylation inhibition in RSC96 Schwann cells with in vivo mouse model

    PMID:34650915 PMID:34804362

    Open questions at the time
    • G-protein switching mechanism in cancer not structurally resolved
    • palmitoylation site on TSHR not mapped
    • Schwann cell findings from single lab
  11. 2022 Medium

    TSH/TSHR signaling was linked to tumor immune evasion by demonstrating that TSHR activation induces PD-L1 expression through an AC-PKA-JNK-c-JUN cascade in thyroid cancer and glioma, with moDCs serving as a local TSH source in the tumor microenvironment.

    Evidence Single-cell transcriptomics, luciferase reporter, and in vivo homograft mouse models with TSHR inhibitor

    PMID:35101946

    Open questions at the time
    • JNK involvement contrasts with other studies showing JNK-independence in adipocytes; cell-type specificity unresolved
    • single-lab finding not independently replicated
  12. 2024 High

    Conditional TSHR deletion in CD8+ TILs proved that tumor-microenvironment TSH/TSHR signaling directly drives T cell exhaustion through PKA/CREB-dependent upregulation of PD-1 and TIM3, while CRC-derived exosomal TSHR transfer was identified as a mechanism increasing receptor levels on T cells.

    Evidence Conditional TSHR knockout in CD8+ T cells, RNA-seq, ChIP, luciferase assay, flow cytometry

    PMID:39285586

    Open questions at the time
    • exosomal TSHR transfer mechanism not structurally characterized
    • whether TSHR-mediated exhaustion operates broadly across tumor types or is context-specific remains unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length TSHR structure including the transmembrane domain and G-protein coupling interfaces has not been solved, and the molecular determinants governing the switch from Gαs to Gα12/13 coupling during cancer dedifferentiation remain undefined.
  • no full-length TSHR cryo-EM or crystal structure available
  • mechanism of G-protein selectivity switch unresolved
  • in vivo validation of exosomal TSHR transfer in immunotherapy settings lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 6 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 6
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 4 R-HSA-1430728 Metabolism 3
Partners
GLIS3GNA12GNA13GNAQGNASLARG

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Crystal structure of TSHR extracellular domain (residues 22-260) bound to blocking-type human monoclonal autoantibody K1-70 solved at 1.9 Å resolution, revealing that K1-70 binds the concave surface of the leucine-rich repeat domain (LRD) in approximately the opposite orientation (~155° rotation) to stimulating autoantibody M22, and more N-terminally on the TSHR concave surface; mutagenesis of interface residues confirmed functional relevance of observed contacts. X-ray crystallography at 1.9 Å + site-directed mutagenesis Journal of molecular endocrinology High 21247981
2015 TSHR signaling stimulates proliferation of orbital fibroblasts in thyroid eye disease via the PI3K/Akt pathway and through induction of miR-146a and miR-155, which reduce expression of anti-proliferative targets ZNRF3 and PTEN; TSHR-specific siRNA knockdown abolished TSH-induced proliferation. siRNA knockdown, BrdU proliferation assay, Western blot, qPCR, PI3K inhibitor (LY294002) Investigative ophthalmology & visual science Medium 31622470
2017 GLIS3 transcription factor acts downstream of TSH/TSHR signaling and is required for TSH/TSHR-mediated thyroid follicular cell proliferation and thyroid hormone biosynthesis; GLIS3 deficiency blocks TSH-mediated activation of the mTORC1/RPS6 pathway and directly regulates iodide transporter genes NIS and PDS. ChIP-Seq, promoter analysis, conditional knockout mouse model, signaling pathway analysis The Journal of clinical investigation High 29083325
2010 Tissue-specific knockout of TSHR in white adipose tissue demonstrated that adipocyte TSHRs are required for normal TSH-induced lipolysis (10-fold lower sensitivity in KO adipocytes) and normal adipocyte size regulation; catecholamine-induced lipolysis was unaffected, indicating TSH-specific signaling through adipocyte TSHR. Cre-loxP conditional knockout (Fabp4-Cre), isolated adipocyte lipolysis assays Biochemical and biophysical research communications High 20152797
2010 TSHR β-subunits (truncated ectodomain constructs) dimerize with full-length TSHR via direct protein-protein interaction, reducing cell-surface expression of full-length receptors and significantly decreasing TSH-induced cAMP generation without altering constitutive cAMP levels; faster internalization of β-subunits was identified as a contributing mechanism. Co-immunoprecipitation, FRET, transfection in HEK293 cells, cAMP assay, flow cytometry Molecular endocrinology High 20719860
2012 TSHR-stimulated cAMP production in orbital fibroblasts from Graves' ophthalmopathy patients is exclusively mediated via TSHR, as demonstrated by complete blockade of rhTSH-, GD-IgG-, and M22-induced cAMP production by the low-molecular-weight TSHR antagonist Org-274179-0 in dose-dependent fashion. cAMP assay, small molecule antagonist pharmacology in differentiated orbital fibroblast cultures The Journal of clinical endocrinology and metabolism Medium 22419705
2007 Posttranslational modifications of TSHR—including sialylation, phosphorylation, glycosylation, and oligomerization—influence TSHR cell-surface expression and signaling; increased sialylation results in increased TSHR cell-surface expression. TSHR also couples to the MAPK pathway through GRKs and arrestins in addition to Gαs and Gαq. Review synthesizing published biochemical studies on TSHR modifications Trends in endocrinology and metabolism Low 17524661
2011 Systematic mutagenesis of 41 residues in the TSHR hinge region identified new TSH contact points including a binding domain from position F381 to D386; negative charge, aromatic, and hydrophilic amino acid properties contribute to hormone-TSHR hinge interaction; same positions affect binding of superagonistic TSH analog TR1401. Site-directed mutagenesis, TSH binding assay, cell surface expression analysis Endocrinology High 21628383
2015 TSH/TSHR signaling suppresses fatty acid synthase (FASN) expression in mature adipocytes via PKA activation, CREB phosphorylation, and ERK1/2 activation; PKA and ERK inhibitors partially abolished TSH-induced FASN downregulation, whereas JNK inhibition had no effect. In vitro adipocyte culture, pharmacological inhibitors (PKA, ERK, JNK), Western blot, RT-PCR Journal of cellular physiology Medium 25655684
2022 TSH activates TSHR to induce tumor PD-L1 expression through the TSHR-AC-PKA-JNK-c-JUN signaling pathway in thyroid cancer and glioma cells; moDCs in the tumor microenvironment are a primary source of TSH; TSHR inhibition reversed tumor immune evasion by reducing PD-L1 expression. Single-cell transcriptomics, transcriptomic sequencing, Western blotting, luciferase reporter, in vivo homograft mouse models, TSHR inhibitor treatment Journal for immunotherapy of cancer Medium 35101946
2024 TSH/TSHR signaling in CD8+ tumor-infiltrating lymphocytes promotes T cell exhaustion through the PKA/CREB signaling pathway, upregulating PD-1 and TIM3; conditional TSHR deletion in CD8+ TILs improved effector differentiation. CRC cells secreted TSHR via exosomes to increase TSHR levels in CD8+ T cells, and MDSCs were identified as the main source of TSH in the tumor microenvironment. Conditional TSHR knockout, RNA-sequencing, Western blotting, ChIP, luciferase assay, immunofluorescence, flow cytometry Cancer communications High 39285586
2000 A novel germline TSHR mutation (Met463Val) in the second membrane-spanning domain causes constitutive activation of the cAMP pathway, producing hereditary non-autoimmune hyperthyroidism; functional studies confirmed ligand-independent cAMP production. Sanger sequencing, functional cAMP assay in transfected cells Thyroid Medium 11201847
2011 TSHR intron 1 SNP rs179247 predisposing allele is associated with significantly lower TSHR mRNA expression in thymus; allele-specific transcript quantification in heterozygotes confirmed that the predisposing allele is expressed at lower level than the protective allele in both thymic epithelial cells and thymocytes, linking impaired central tolerance to Graves' disease susceptibility. Quantitative PCR, allele-specific transcript quantification in thymic tissue Human molecular genetics Medium 21642385
2015 TSHR is expressed and functional in thymocytes; Graves' disease stimulating autoantibodies (TSAbs) can stimulate thymocytes through TSHR, as demonstrated by functional signaling assays; TSHR expression is confined to maturing thymocytes. Protein immunoblotting, quantitative PCR, functional signaling assays Journal of immunology Medium 25801430
2011 Inactivating TSHR mutations can selectively abrogate Gq-coupled signaling while partially retaining Gs-coupled signaling (as shown for R450H); this differential coupling defect (Gq-dominant) correlates with a paradoxical non-classic phenotype of high radioiodine uptake in TSH resistance patients. In vitro expression of mutant TSHRs with cAMP assay (Gs) and alternative pathway assays (Gq) in transfected cells The Journal of clinical endocrinology and metabolism Medium 21677043
2021 TSH/TSHR signaling in Schwann cells (RSC96) induces oxidative stress, mitochondrial dysfunction, and apoptosis; TSHR knockout or inhibition of TSHR palmitoylation alleviated TSH-induced apoptosis, identifying palmitoylation as a post-translational modification regulating TSHR function in Schwann cells. TSHR knockout, inhibition of palmitoylation, oxidative stress assays, apoptosis assay, in vivo mouse model Oxidative medicine and cellular longevity Medium 34804362
2016 Thyrostimulin-TSHR signaling promotes ovarian cancer cell proliferation via PKA-independent trans-activation of EGFR, requiring MEK-ERK and PI3K-AKT cascades; pharmacological dissection with multiple inhibitors confirmed pathway requirements. Cell proliferation assays, pharmacological inhibitors (PKA, MEK, PI3K, EGFR), signaling assays in NIH:OVCAR-3 cells Scientific reports Medium 27273257
2012 PDGF-AB and PDGF-BB (but not PDGF-AA) increase TSHR expression on orbital fibroblasts; upregulated TSHR expression amplifies cAMP-mediated inflammatory cytokine (IL-6, IL-8, CCL2) and hyaluronan production in response to TSH and Graves' disease IgGs; TSHR blocking antibody K1-70 and cAMP inhibitor H89 confirmed TSHR/cAMP dependence. Flow cytometry, ELISA, TSHR blocking antibody and cAMP inhibitor pharmacology in primary orbital fibroblasts The Journal of clinical endocrinology and metabolism Medium 22438231
2021 In thyroid cancer cells undergoing dedifferentiation, TSH/TSHR preferentially couples to Gα12/13 (rather than canonical Gαs), activating RhoA via LARG (leukemia-associated RhoA GEF), promoting a pro-migratory phenotype; PI3K/AKT/mTOR signaling enhances Gα12/13 signaling by increasing LARG levels while inhibiting Gαs signaling and thyroid-specific gene expression. Signaling pathway analysis, Western blotting, LARG expression studies in thyroid cancer cell lines Frontiers in oncology Medium 34650915
2018 Liver-specific conditional knockout of TSHR reduced hepatic triglyceride and cholesterol contents by modifying synthesis and catabolism of lipids and decreased serum LDL-C, while systemic energy metabolism was unaffected, demonstrating a direct role for hepatic TSHR in liver lipid metabolism. Cre/LoxP conditional liver-specific knockout, lipid measurements, metabolic chamber analysis Biochemical and biophysical research communications High 29421660
2008 Novel TSHR mutations (P27T, E34K, R46P, D403N, W488R, M527T) identified in congenital hypothyroidism patients were functionally characterized: R46P and W488R completely abolished TSH binding and cAMP response; E34K, D403N, and M527T showed reduced cAMP response and TSH binding capacity, confirming their loss-of-function nature. Site-directed mutagenesis, cAMP assay, 125I-TSH binding assay, microchip flow cytometry in COS cells Clinical endocrinology High 18727713
2023 PFOA reduces TSHR mRNA expression and impairs TSHR N-glycosylation in thyroid follicular cells, disrupting TSH-activated cAMP/CREB signaling and downstream transcription of thyroid-specific genes (NIS, TG, TPO); forskolin treatment (bypassing TSHR) rescued CREB phosphorylation, confirming TSHR as the disruption target. qPCR, Western blot, cAMP assay, CREB phosphorylation, glycosylation analysis, forskolin rescue experiment in FRTL-5 cells Environmental research Medium 37827365
2012 TSHR knockdown in 3T3-L1 preadipocytes blocked adipocyte differentiation as assessed by Oil-Red-O staining and reduced expression of PPARγ and ALBP; TSHR expression was upregulated during adipogenesis, establishing a required role for TSHR in adipocyte differentiation. siRNA knockdown, Oil-Red-O staining, RT-PCR in 3T3-L1 cells Lipids in health and disease Medium 22289392
1998 The N-terminal segment of the TSHR extracellular domain (residues 9-165, particularly 90-165) is required not only as a functional epitope for Graves' TSHRAbs but also for induction of TSHRAbs in an animal model; mice immunized with TSHR chimeras lacking this N-terminal region failed to develop TSHRAbs. TSHR/LH-CGR chimeric receptor immunization in AKR/N mice, TBII and TBAb functional assays Endocrinology Medium 9528975

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves' ophthalmopathy patients. Clinical endocrinology 196 12608932
2015 A brain circuit that synchronizes growth and maturation revealed through Dilp8 binding to Lgr3. Science (New York, N.Y.) 136 26429885
2015 Drosophila Lgr3 Couples Organ Growth with Maturation and Ensures Developmental Stability. Current biology : CB 136 26441350
2005 Association of the TSHR gene with Graves' disease: the first disease specific locus. European journal of human genetics : EJHG 134 16106256
2004 Dry eye syndrome in thyroid-associated ophthalmopathy: lacrimal expression of TSH receptor suggests involvement of TSHR-specific autoantibodies. Acta ophthalmologica Scandinavica 127 15115450
2015 Dilp8 requires the neuronal relaxin receptor Lgr3 to couple growth to developmental timing. Nature communications 125 26510564
2011 Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. Journal of molecular endocrinology 100 21247981
2009 Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease. Human molecular genetics 100 19244275
2007 Effects of serum TSH and FT4 levels and the TSHR-Asp727Glu polymorphism on bone: the Rotterdam Study. Clinical endocrinology 98 17803697
2015 Genetic predisposition to papillary thyroid carcinoma: involvement of FOXE1, TSHR, and a novel lincRNA gene, PTCSC2. The Journal of clinical endocrinology and metabolism 86 25303483
2012 Role of extrathyroidal TSHR expression in adipocyte differentiation and its association with obesity. Lipids in health and disease 84 22289392
1993 The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: structural studies of the TSH-R and the alpha-subunit of Gs in human thyroid neoplasms. The Journal of clinical endocrinology and metabolism 76 8501149
2017 Effects of Long-Term In Vivo Exposure to Di-2-Ethylhexylphthalate on Thyroid Hormones and the TSH/TSHR Signaling Pathways in Wistar Rats. International journal of environmental research and public health 70 28054989
2016 Growth Coordination During Drosophila melanogaster Imaginal Disc Regeneration Is Mediated by Signaling Through the Relaxin Receptor Lgr3 in the Prothoracic Gland. Genetics 68 27558136
2017 GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation. The Journal of clinical investigation 62 29083325
2019 TSHR Signaling Stimulates Proliferation Through PI3K/Akt and Induction of miR-146a and miR-155 in Thyroid Eye Disease Orbital Fibroblasts. Investigative ophthalmology & visual science 58 31622470
2001 A comprehensive analysis of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in familial nonmedullary thyroid cancer: confirmation of linkage to TCO1. The Journal of clinical endocrinology and metabolism 58 11502798
2021 Tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding neuropeptides via Lgr3/8 in the brain. Nature cell biology 57 33558728
2010 Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations. European journal of endocrinology 57 20926595
2011 Association of an SNP with intrathymic transcription of TSHR and Graves' disease: a role for defective thymic tolerance. Human molecular genetics 56 21642385
2009 Clinical associations of the genetic variants of CTLA-4, Tg, TSHR, PTPN22, PTPN12 and FCRL3 in patients with Graves' disease. Clinical endocrinology 55 19438904
2010 Genetics of thyroid autoimmunity and the role of the TSHR. Molecular and cellular endocrinology 51 20083159
2000 Novel TSHR germline mutation (Met463Val) masquerading as Graves' disease in a large Welsh kindred with hyperthyroidism. Thyroid : official journal of the American Thyroid Association 51 11201847
2018 The biology and evolution of the Dilp8-Lgr3 pathway: A relaxin-like pathway coupling tissue growth and developmental timing control. Mechanisms of development 50 29715504
2022 TSH-TSHR axis promotes tumor immune evasion. Journal for immunotherapy of cancer 49 35101946
2008 Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain. European journal of endocrinology 46 18694911
2010 Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARβ2 genes in papillary thyroid carcinoma. Medical oncology (Northwood, London, England) 44 20535589
2015 Mechanisms of Action of TSHR Autoantibodies. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 41 26361260
2010 Tissue-specific knockout of TSHr in white adipose tissue increases adipocyte size and decreases TSH-induced lipolysis. Biochemical and biophysical research communications 41 20152797
2016 Sex-specific regulation of Lgr3 in Drosophila neurons. Proceedings of the National Academy of Sciences of the United States of America 40 26884206
1993 Dual mechanism of perturbation of thyrotropin-mediated activation of thyroid cells by antibodies to the thyrotropin receptor (TSHR) and TSHR-derived peptides. The Journal of clinical endocrinology and metabolism 40 8103771
2023 A review of TSHR- and IGF-1R-related pathogenesis and treatment of Graves' orbitopathy. Frontiers in immunology 37 36742308
2022 CAR-T Cells Targeting TSHR Demonstrate Safety and Potent Preclinical Activity Against Differentiated Thyroid Cancer. The Journal of clinical endocrinology and metabolism 37 34751400
2012 PDGF enhances orbital fibroblast responses to TSHR stimulating autoantibodies in Graves' ophthalmopathy patients. The Journal of clinical endocrinology and metabolism 36 22438231
2012 Complete inhibition of rhTSH-, Graves' disease IgG-, and M22-induced cAMP production in differentiated orbital fibroblasts by a low-molecular-weight TSHR antagonist. The Journal of clinical endocrinology and metabolism 34 22419705
2012 A TSHR-LH/CGR chimera that measures functional thyroid-stimulating autoantibodies (TSAb) can predict remission or recurrence in Graves' patients undergoing antithyroid drug (ATD) treatment. The Journal of clinical endocrinology and metabolism 33 22492869
2010 Thyroid stimulating hormone receptor (TSHR) intron 1 variants are major risk factors for Graves' disease in three European Caucasian cohorts. PloS one 33 21124799
2007 Modulation of TSHR signaling by posttranslational modifications. Trends in endocrinology and metabolism: TEM 33 17524661
2017 TSHR as a therapeutic target in Graves' disease. Expert opinion on therapeutic targets 32 28127991
1994 Induction of thyrotropin receptor (TSH-R) autoantibodies and thyroiditis in mice immunised with the recombinant TSH-R. Biochemical and biophysical research communications 32 8135775
2015 Genetics of Graves' Disease: Special Focus on the Role of TSHR Gene. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 31 26361261
2014 Epigenetic silencing of TSHR gene in thyroid cancer patients in relation to their BRAF V600E mutation status. Endocrine 31 24927793
2011 Molecular screening of the TSH receptor (TSHR) and thyroid peroxidase (TPO) genes in Korean patients with nonsyndromic congenital hypothyroidism. Clinical endocrinology 30 21707688
2024 Local TSH/TSHR signaling promotes CD8+ T cell exhaustion and immune evasion in colorectal carcinoma. Cancer communications (London, England) 28 39285586
2016 Next-generation sequencing analysis of TSHR in 384 Chinese subclinical congenital hypothyroidism (CH) and CH patients. Clinica chimica acta; international journal of clinical chemistry 27 27637299
1998 The formation of thyrotropin receptor (TSHR) antibodies in a Graves' animal model requires the N-terminal segment of the TSHR extracellular domain. Endocrinology 27 9528975
2021 TSH Combined with TSHR Aggravates Diabetic Peripheral Neuropathy by Promoting Oxidative Stress and Apoptosis in Schwann Cells. Oxidative medicine and cellular longevity 26 34804362
2011 Nonclassic TSH resistance: TSHR mutation carriers with discrepantly high thyroidal iodine uptake. The Journal of clinical endocrinology and metabolism 26 21677043
2015 Graves' disease TSHR-stimulating antibodies (TSAbs) induce the activation of immature thymocytes: a clue to the riddle of TSAbs generation? Journal of immunology (Baltimore, Md. : 1950) 24 25801430
2011 Small molecule TSHR agonists and antagonists. Annales d'endocrinologie 24 21511239
2016 Thyrostimulin-TSHR signaling promotes the proliferation of NIH:OVCAR-3 ovarian cancer cells via trans-regulation of the EGFR pathway. Scientific reports 23 27273257
2001 Consequences of hypothyroidism on auditory system function in Tshr mutant (hyt) mice. Journal of the Association for Research in Otolaryngology : JARO 23 11833606
1996 Yersinia enterocolitica envelope proteins that are crossreactive with the thyrotropin receptor (TSHR) also have B-cell mitogenic activity. Journal of autoimmunity 23 8864826
2013 Examination of orbital tissues in murine models of Graves' disease reveals expression of UCP-1 and the TSHR in retrobulbar adipose tissues. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 22 23386414
2019 Mutation screening of the TSHR gene in 220 Chinese patients with congenital hypothyroidism. Clinica chimica acta; international journal of clinical chemistry 21 31356790
2018 Analysis of chosen polymorphisms rs2476601 a/G - PTPN22, rs1990760 C/T - IFIH1, rs179247 a/G - TSHR in pathogenesis of autoimmune thyroid diseases in children. Autoimmunity 21 29973096
2017 Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis. Clinica chimica acta; international journal of clinical chemistry 21 28455095
2015 TSH/TSHR Signaling Suppresses Fatty Acid Synthase (FASN) Expression in Adipocytes. Journal of cellular physiology 21 25655684
2013 Follicular variant of papillary thyroid carcinoma presenting as toxic nodule in an adolescent: coexistent polymorphism of the TSHR and Gsα genes. Thyroid : official journal of the American Thyroid Association 21 22985488
2023 Perfluorooctanoic acid disrupts thyroid-specific genes expression and regulation via the TSH-TSHR signaling pathway in thyroid cells. Environmental research 20 37827365
2017 Simultaneous induction of Graves' hyperthyroidism and Graves' ophthalmopathy by TSHR genetic immunization in BALB/c mice. PloS one 20 28319174
2017 Association between monoallelic TSHR mutations and congenital hypothyroidism: a statistical approach. European journal of endocrinology 20 29092890
2012 Adoptive transfer of antithyrotropin receptor (TSHR) autoimmunity from TSHR knockout mice to athymic nude mice. Endocrinology 20 22334716
2008 Functional studies of new TSH receptor (TSHr) mutations identified in patients affected by hypothyroidism or isolated hyperthyrotrophinaemia. Clinical endocrinology 19 18727713
2014 Association between polymorphisms in the TSHR gene and Graves' orbitopathy. PloS one 18 25061884
2019 Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms. Frontiers in immunology 17 31379878
2018 Liver-specific deletion of TSHR inhibits hepatic lipid accumulation in mice. Biochemical and biophysical research communications 17 29421660
2017 Downregulated expression of TSHR is associated with distant metastasis in thyroid cancer. Oncology letters 17 29344196
2017 Luteolin suppresses tumor progression through lncRNA BANCR and its downstream TSHR/CCND1 signaling in thyroid carcinoma. International journal of clinical and experimental pathology 17 31966836
2020 Nevirapine Increases Sodium/Iodide Symporter-Mediated Radioiodide Uptake by Activation of TSHR/cAMP/CREB/PAX8 Signaling Pathway in Dedifferentiated Thyroid Cancer. Frontiers in oncology 16 32300552
2015 Methylation status of TSHr in well-differentiated thyroid cancer by using cytologic material. BMC cancer 16 26519197
2023 TSHR-based chimeric antigen receptor T cell specifically deplete auto-reactive B lymphocytes for treatment of autoimmune thyroid disease. International immunopharmacology 15 37690235
2016 TSHR Gene Polymorphisms in the Enhancer Regions Are Most Strongly Associated with the Development of Graves' Disease, Especially Intractable Disease, and of Hashimoto's Disease. Thyroid : official journal of the American Thyroid Association 15 27762730
2010 Subunit interactions influence TSHR multimerization. Molecular endocrinology (Baltimore, Md.) 15 20719860
2018 Association of BRAF gene and TSHR with cervical lymph node metastasis of papillary thyroid microcarcinoma. Oncology letters 14 30655754
2015 Mutations of TSHR and TP53 Genes in an Aggressive Clear Cell Follicular Carcinoma of the Thyroid. Endocrine pathology 14 26260781
2007 Preliminary evidence for interaction of PTPN12 polymorphism with TSHR genotype and association with Graves' ophthalmopathy. Clinical endocrinology 14 17608818
2018 Concurrent TSHR mutations and DIO2 T92A polymorphism result in abnormal thyroid hormone metabolism. Scientific reports 13 29973617
2008 A novel TSHR gene mutation (Ile691Phe) in a Chinese family causing autosomal dominant non-autoimmune hyperthyroidism. Journal of human genetics 13 18306976
2023 Thyroid-stimulating hormone receptor (TSHR) as a target for imaging differentiated thyroid cancer. Surgery 12 37919223
2022 Capsaicin restores sodium iodine symporter-mediated radioiodine uptake through bypassing canonical TSH‒TSHR pathway in anaplastic thyroid carcinoma cells. Journal of molecular cell biology 12 34751390
2022 Sinomenine Hydrochloride Promotes TSHR-Dependent Redifferentiation in Papillary Thyroid Cancer. International journal of molecular sciences 12 36142613
2021 Crosstalk Between Abnormal TSHR Signaling Activation and PTEN/PI3K in the Dedifferentiation of Thyroid Cancer Cells. Frontiers in oncology 12 34650915
2020 Association between TSHR gene methylation and papillary thyroid cancer: a meta-analysis. Endocrine 12 32279226
2014 A deletion including exon 2 of the TSHR gene is associated with thyroid dysgenesis and severe congenital hypothyroidism. Journal of pediatric endocrinology & metabolism : JPEM 12 24690939
1996 The gene for the thyrotropin receptor (TSHR) as a candidate gene for congenital hypothyroidism with thyroid dysgenesis. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 12 8981017
2021 Functional differences between TSHR alleles associate with variation in spawning season in Atlantic herring. Communications biology 11 34172814
2020 Clinical diagnostic performance of a fully automated TSI immunoassay vs. that of an automated anti‑TSHR immunoassay for Graves' disease: a Chinese multicenter study. Endocrine 11 32562184
2016 Upregulation of TSHR, TTF-1, and PAX8 in Nodular Goiter Is Associated with Iodine Deficiency in the Follicular Lumen. International journal of endocrinology 11 27525008
2014 Controversial constitutive TSHR activity: patients, physiology, and in vitro characterization. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 11 24845969
2010 Genetic defects, thyroid growth and malfunctions of the TSHR in pediatric patients. Frontiers in bioscience (Landmark edition) 11 20515734
2010 Current standards, variations, and pitfalls for the determination of constitutive TSHR activity in vitro. Methods in enzymology 11 21050930
2018 Mutation screening in the genes PAX-8, NKX2-5, TSH-R, HES-1 in cohort of 63 Brazilian children with thyroid dysgenesis. Archives of endocrinology and metabolism 10 30304112
2013 Epitope recognition in HLA-DR3 transgenic mice immunized to TSH-R protein or peptides. Endocrinology 10 23592747
2024 PET Imaging of Differentiated Thyroid Cancer with TSHR-Targeted [89Zr]Zr-TR1402. Molecular pharmaceutics 9 38976794
2017 Novel germline mutation (Leu512Met) in the thyrotropin receptor gene (TSHR) leading to sporadic non-autoimmune hyperthyroidism. Journal of pediatric endocrinology & metabolism : JPEM 9 28195550
2017 Analytical and Clinical Validation of Two Commercially Available Immunoassays Used in the Detection of TSHR Antibodies. The journal of applied laboratory medicine 9 33636837
2012 A somatic TSHR mutation in a patient with lung adenocarcinoma with bronchioloalveolar carcinoma, coronary artery disease and severe chronic obstructive pulmonary disease. Oncology reports 9 22842620
2011 Identification of novel TSH interaction sites by systematic binding analysis of the TSHR hinge region. Endocrinology 9 21628383
1997 Genetic alterations in N-bis(2-hydroxypropyl)nitrosamine-induced rat transplantable thyroid carcinoma lines: analysis of the TSH-R, G(alpha)s, ras and p53 genes. Carcinogenesis 9 9054617